Ethical Considerations in Neurogenetic Testing

2018 ◽  
Vol 38 (05) ◽  
pp. 505-514 ◽  
Author(s):  
Xiaowei Su ◽  
Zachary Simmons
Keyword(s):  
Genetic Testing ◽  
Ethical Issues ◽  
Diagnostic Testing ◽  
Ethical Principles ◽  
Ethical Framework ◽  
Complex Nature ◽  
Neurologic Diseases ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
The One

AbstractRecent advances in the genetics of neurologic diseases coupled with improvements in sensitivity and specificity are making genetic testing an increasingly important part of diagnosis and management for neurologists. However, the complex nature of genetic testing, the nuances of multiple result types, and the short- and long-term consequences of genetic diagnoses raise important ethical issues for the clinician. Neurologists must balance the ethical principles of beneficence and nonmaleficence, on the one hand, with patient autonomy on the other hand, when ordering such tests by facilitating shared decision making, carrying out their fiduciary responsibilities to patients, and ensuring that patients have adequate counseling to make informed decisions. This review summarizes ethical issues related to genetic testing for neurologic diseases, with a focus on clinical practice. Informed consent for genetic testing of patients and asymptomatic at-risk family members is discussed. The roles and responsibilities of physicians as genetic counselors are reviewed, including the framing of incidental findings and variants of unknown significance that impact individuals' decisions about whether to pursue genetic testing and what results they wish to know. Disclosure and its consequences for the patient are placed within an ethical framework to permit a better understanding of why genetic testing is different from most other diagnostic testing ordered by physicians. The review ends with clinical vignettes that attempt to place ethical principles into familiar clinical settings involving physicians, patients and their families.

scholarly journals Germline mutations in the new E1’ cryptic exon of the VHL gene in patients with tumours of von Hippel-Lindau disease spectrum or with paraganglioma

2020 ◽  
Vol 57 (11) ◽  
pp. 752-759 ◽  
Author(s):  
Alexandre Buffet ◽  
Bruna Calsina ◽  
Shahida Flores ◽  
Sophie Giraud ◽  
Marion Lenglet ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Diagnostic Testing ◽  
Germline Mutations ◽  
Cryptic Exon ◽  
Von Hippel Lindau ◽  
Variants Of Unknown Significance ◽  
Disease Spectrum ◽  
Unknown Significance ◽  
Next Generation Sequencing Ngs ◽  
Vhl Disease

BackgroundsThe incidence of germline mutations in the newly discovered cryptic exon (E1’) of VHL gene in patients with von Hippel-Lindau (VHL) disease and in patients with paraganglioma or pheochromocytoma (PPGL) is not currently known.MethodsWe studied a large international multicentre cohort of 1167 patients with a previous negative genetic testing. Germline DNA from 75 patients with a single tumour of the VHL spectrum (‘Single VHL tumour’ cohort), 70 patients with multiple tumours of the VHL spectrum (‘Multiple VHL tumours’ cohort), 76 patients with a VHL disease as described in the literature (‘VHL-like’ cohort) and 946 patients with a PPGL were screened for E1’ genetic variants.ResultsSix different genetic variants in E1' were detected in 12 patients. Two were classified as pathogenic, 3 as variants of unknown significance and 1 as benign. The rs139622356 was found in seven unrelated patients but described in only 16 patients out of the 31 390 of the Genome Aggregation Database (p<0.0001) suggesting that this variant might be either a recurrent mutation or a modifier mutation conferring a risk for the development of tumours and cancers of the VHL spectrum.ConclusionsVHL E1’ cryptic exon mutations contribute to 1.32% (1/76) of ‘VHL-like’ cohort and to 0.11% (1/946) of PPGL cohort and should be screened in patients with clinical suspicion of VHL, and added to panels for Next Generation Sequencing (NGS) diagnostic testing of hereditary PPGL. Our data highlight the importance of studying variants identified in deep intronic sequences, which would have been missed by examining only coding sequences of genes/exomes. These variants will likely be more frequently detected and studied with the upcoming implementation of whole-genome sequencing into clinical practice.

scholarly journals An Ethical Framework for the Design, Development, Implementation, and Assessment of Drones Used in Public Healthcare

2020 ◽  
Vol 26 (5) ◽  
pp. 2867-2891 ◽  
Author(s):  
Dylan Cawthorne ◽  
Aimee Robbins-van Wynsberghe
Keyword(s):  
Artificial Intelligence ◽  
Ethical Issues ◽  
Applied Ethics ◽  
Human Values ◽  
Ethical Principles ◽  
Ethical Framework ◽  
Public Healthcare ◽  
Social Experiment ◽  
Design Development ◽  
Ethical Guidelines

Abstract The use of drones in public healthcare is suggested as a means to improve efficiency under constrained resources and personnel. This paper begins by framing drones in healthcare as a social experiment where ethical guidelines are needed to protect those impacted while fully realizing the benefits the technology offers. Then we propose an ethical framework to facilitate the design, development, implementation, and assessment of drones used in public healthcare. Given the healthcare context, we structure the framework according to the four bioethics principles: beneficence, non-maleficence, autonomy, and justice, plus a fifth principle from artificial intelligence ethics: explicability. These principles are abstract which makes operationalization a challenge; therefore, we suggest an approach of translation according to a values hierarchy whereby the top-level ethical principles are translated into relevant human values within the domain. The resulting framework is an applied ethics tool that facilitates awareness of relevant ethical issues during the design, development, implementation, and assessment of drones in public healthcare.

The incidence of BRCA1 and BRCA2 variants of unknown significance varies in different ethnic populations

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10002-10002 ◽  
Author(s):  
D. M. Opatt ◽  
M. Morrow ◽  
M. Daly
Keyword(s):  
Breast Cancer ◽  
African American ◽  
Genetic Testing ◽  
African American Women ◽  
White Women ◽  
Personal History ◽  
Brca1 And Brca2 ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
History Of

10002 Background: BRCA1 and BRCA2 mutations in the general population are rare. Women with these mutations have a significantly increased risk of invasive breast and ovarian cancer (65–85% and 15–65% cumulative lifetime risk, respectively). Variants of unknown significance (VUS), which are of uncertain clinical importance, account for up to 50% of all identified BRCA1 and BRCA2 sequence alterations1. Methods: Pooled data from all patients presenting to Fox Chase Cancer Center for genetic counseling was examined. Patients underwent genetic testing after detailed genetic counseling. Clinical data, including gender, ethnic background, and personal history of cancer, and total number of patients tested were collected. Results: A total of 1,765 women and 236 men underwent genetic testing. The distribution of ethnicity was: <1% Asian, 2.7% African American, <1% Hispanic, 2.4% other or of more than one ethnicity, 83% White, and 11% unknown. Mutations of BRCA1 and BRCA2 were seen in 13% of the women and 2.7% of the men. VUS were seen in 6.2% of the women and .15% of the men. Of the women positive for a VUS, 2.4% were Asian, 18.1% were African American, 5.5% were Hispanic, 4.7% were more than one ethnicity, 66.9% were White, and 2.4% were Unknown ethnicity. Only .15% of the men tested were positive for a VUS, all of whom were White. Of the 51 African American women tested, 45.1% were positive for a VUS while only 5.5% of the 1,503 White women tested were positive (p<0.0001). Of the females testing positive for a VUS, a personal history of breast cancer was seen in 66.7% of Asians, 78.3% of African Americans, 100% of Hispanics, 83.3% of those more than one race, 61% of Whites, and none of the people of unknown ethnic origin. One of three men testing positive for a VUS reported a history of breast cancer. Conclusions: Identification of VUS occurred disproportionately in African Americans, occurring ten times more often in African American women than White women in our study. Studies to improve classification of VUS as deleterious or neutral are needed to enhance the utility of genetic testing for women at risk, particularly those of African American ethnicity. 1Goldman, DE et al. Am. J. Hum. Genet., 2004. No significant financial relationships to disclose.

Choosing Education

2019 ◽  
pp. 243-251
Author(s):  
Robert L. Klitzman
Keyword(s):  
Ethical Issues ◽  
Considerable Effort ◽  
Knowledge Gaps ◽  
Psychological Issues ◽  
The Public ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Recessive Genes ◽  
Basic Biology

Physicians in several fields, patients, families, and the public at large would benefit from more education and understanding regarding infertility and its treatment—from information about basic biology and causes of infertility to specific procedures and the ethical, legal, social, and psychological issues that can arise. Patients must comprehend myriad new facts, which can take considerable effort, struggling to grasp important aspects of statistics and genetics, including recessive genes and variants of unknown significance. Many physicians in and outside of the field of infertility also have knowledge gaps about these medical (e.g., genetic), psychological, and ethical issues and vary in how well they educate patients.

scholarly journals Facilitations and Hurdles of Genetic Testing in Neuromuscular Disorders

Diagnostics ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 701
Author(s):  
Andrea Barp ◽  
Lorena Mosca ◽  
Valeria Ada Sansone
Keyword(s):  
Genetic Testing ◽  
Neuromuscular Disorders ◽  
Single Nucleotide Variants ◽  
Gene Therapies ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
New Gene ◽  
Genetic Techniques ◽  
Definition Of ◽  
Next Generation Sequencing Ngs

Neuromuscular disorders (NMDs) comprise a heterogeneous group of disorders that affect about one in every thousand individuals worldwide. The vast majority of NMDs has a genetic cause, with about 600 genes already identified. Application of genetic testing in NMDs can be useful for several reasons: correct diagnostic definition of a proband, extensive familial counselling to identify subjects at risk, and prenatal diagnosis to prevent the recurrence of the disease; furthermore, identification of specific genetic mutations still remains mandatory in some cases for clinical trial enrollment where new gene therapies are now approaching. Even though genetic analysis is catching on in the neuromuscular field, pitfalls and hurdles still remain and they should be taken into account by clinicians, as for example the use of next generation sequencing (NGS) where many single nucleotide variants of “unknown significance” can emerge, complicating the correct interpretation of genotype-phenotype relationship. Finally, when all efforts in terms of molecular analysis have been carried on, a portion of patients affected by NMDs still remain “not genetically defined”. In the present review we analyze the evolution of genetic techniques, from Sanger sequencing to NGS, and we discuss “facilitations and hurdles” of genetic testing which must always be balanced by clinicians, in order to ensure a correct diagnostic definition, but taking always into account the benefit that the patient could obtain especially in terms of “therapeutic offer”.

scholarly journals The underestimated burden of monogenic kidney disease in adults waitlisted for kidney transplantation

2021 ◽  
Author(s):  
Eva Schrezenmeier ◽  
Elisa Kremerskothen ◽  
Fabian Halleck ◽  
Oliver Staeck ◽  
Lutz Liefeldt ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Genetic Testing ◽  
Kidney Disease ◽  
Diagnostic Value ◽  
Considerable Proportion ◽  
Major Health ◽  
Variants Of Unknown Significance ◽  
Health Care Burden ◽  
Unknown Significance ◽  
Next Generation Sequencing Ngs

Abstract Purpose Chronic kidney disease (CKD) is a major health-care burden. Increasing evidence suggests that a considerable proportion of patients are affected by a monogenic kidney disorder. Methods In this study, the kidney transplantation waiting list at the Charité was screened for patients with undetermined cause of CKD. By next-generation sequencing (NGS) we targeted all 600 genes described and associated with kidney disease or allied disorders. Results In total, 635 patients were investigated. Of these, 245 individuals had a known cause of CKD (38.5%) of which 119 had a proven genetic disease (e.g., ADPKD, Alport). The other 340 patients (53.5%) were classified as undetermined diagnosis, of whom 87 had kidney failure (KF) onset <40 years. To this latter group genetic testing was offered as well as to those patients (n = 29) with focal segmental glomerulosclerosis (FSGS) and all individuals (n = 21) suspicious for thrombotic microangiopathy (TMA) in kidney biopsy. We detected diagnostic variants in 26 of 126 patients (20.6%) of which 14 of 126 (11.1%) were pathogenic or likely pathogenic. In another 12 of 126 (9.5%) patients, variants of unknown significance (VUS) were detected. Conclusion Our study demonstrates the diagnostic value of comprehensive genetic testing among patients with undetermined CKD.

scholarly journals In silico analysis of BRCA1 and BRCA2 missense variants and the relevance in molecular genetic testing

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kok-Siong Poon
Keyword(s):  
Genetic Testing ◽  
Molecular Genetic ◽  
In Silico Analysis ◽  
Molecular Testing ◽  
Brca1 And Brca2 ◽  
Missense Variants ◽  
Variants Of Unknown Significance ◽  
Sorting Intolerant From Tolerant ◽  
Unknown Significance ◽  
High Concordance

AbstractOver the years since the genetic testing of BRCA1 and BRCA2 has been conducted for research and later introduced into clinical practice, a high number of missense variants have been reported in the literature and deposited in public databases. Polymorphism Phenotyping v2 (PolyPhen-2) and Sorting Intolerant from Tolerant (SIFT) are two widely applied bioinformatics tools used to assess the functional impacts of missense variants. A total of 2605 BRCA1 and 4763 BRCA2 variants from the ClinVar database were analysed with PolyPhen2 and SIFT. When SIFT was evaluated alongside PolyPhen-2 HumDiv and HumVar, it had shown top performance in terms of negative predictive value (NPV) (100%) and sensitivity (100%) for ClinVar classified benign and pathogenic BRCA1 variants. Both SIFT and PolyPhen-2 HumDiv achieved 100% NPV and 100% sensitivity in prediction of pathogenicity of the BRCA2 variants. Agreement was achieved in prediction outcomes from the three tested approaches in 55.04% and 68.97% of the variants of unknown significance (VUS) for BRCA1 and BRCA2, respectively. The performances of PolyPhen-2 and SIFT in predicting functional impacts varied across the two genes. Due to lack of high concordance in prediction outcomes among the two tested algorithms, their usefulness in classifying the pathogenicity of VUS identified through molecular testing of BRCA1 and BRCA2 is hence limited in the clinical setting.

Genetic risk assessment for hereditary RCC: Report from the consensus panel meeting.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 615-615
Author(s):  
Michael Daneshvar ◽  
Neil Mendhiratta ◽  
Ramaprasad Srinivasan ◽  
Eric Jonasch ◽  
Mark Wayne Ball ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Genetic Testing ◽  
Kidney Cancer ◽  
Genetic Risk ◽  
Genetic Counselors ◽  
Genetic Risk Assessment ◽  
Variants Of Unknown Significance ◽  
Modified Delphi ◽  
Unknown Significance ◽  
Patient Advocates

615 Background: While many genes are now known to be associated with hereditary kidney cancer syndromes, there is a paucity of guidelines or uniform consensus on genetic testing for these patients. An expert panel was organized to assess who, what, when and how patients should be evaluated and what testing should be initiated. Methods: A national, multidisciplinary, panel of experts in urology, medical oncology, clinical geneticists, genetic counselors and patient advocates with background and knowledge in hereditary syndromic kidney cancer convened in person in September 2019. A renal cell carcinoma (RCC) genetic risk assessment questionnaire consisting of 52 questions was compiled prior to the meeting using modified Delphi methodology. The questions were then discussed and reviewed with uniform consensus defined as a minimum of 85% agreement in accordance with the National Comprehensive Cancer Network criteria. Results: The panel consisted of twenty-six attendees represented by urologists (43%), medical oncologist (23%), genetic counselors (13%), clinical geneticists (7%), and patient advocates (3%). The questionnaire consisted of fifty-five statements focusing on who, what, when and how genetic testing should be performed in a patient suspected of hereditary RCC syndrome. A >85% agreement was reached on 30/52 statements with 18/25 (72%) achieving consensus addressing “who”, 2/6 (33%) achieving consensus in “what’ category, 2/7 (29%) in ‘when’ and 4/6 (67%) on how. The questions with least consensus were found in the “what/when?” category with only 4/13 questions with minimum 85% agreement. Specific areas of debate included an age cutoff for prompting a genetic risk assessment as well as need for familial testing in patients with variants of unknown significance. Conclusions: Despite experience of the panel in management of hereditary RCC, the consensus was reached only on 66% of genetic testing. While many issues will need to be discussed further, those statements with consensus may be used to guide physicians and patients on who, what, when and how genetic RCC risk assessment should be performed.

scholarly journals Ethical Framework for Designing Autonomous Intelligent Systems

2019 ◽  
Vol 5 (1) ◽  
pp. 18 ◽  
Author(s):  
Jaana Leikas ◽  
Raija Koivisto ◽  
Nadezhda Gotcheva
Keyword(s):  
Intelligent Systems ◽  
Ethical Issues ◽  
Autonomous Systems ◽  
Ethical Principles ◽  
Ethical Framework ◽  
Concept Design ◽  
Systematic Analysis ◽  
Ethical Thought ◽  
Multidisciplinary Perspective ◽  
Fundamental Values

To gain the potential benefit of autonomous intelligent systems, their design and development need to be aligned with fundamental values and ethical principles. We need new design approaches, methodologies and processes to deploy ethical thought and action in the contexts of autonomous intelligent systems. To open this discussion, this article presents a review of ethical principles in the context of artificial intelligence design, and introduces an ethical framework for designing autonomous intelligent systems. The framework is based on an iterative, multidisciplinary perspective yet a systematic discussion during an Autonomous Intelligent Systems (AIS) design process, and on relevant ethical principles for the concept design of autonomous systems. We propose using scenarios as a tool to capture the essential user’s or stakeholder’s specific qualitative information, which is needed for a systematic analysis of ethical issues in the specific design case.

Web-Based Bioinformatics Predictors: Recommendations to Assess Lysosomal Cholesterol Trafficking Diseases-Related Genes

2019 ◽  
Vol 58 (01) ◽  
pp. 050-059 ◽  
Author(s):  
Laura López de Frutos ◽  
Jorge J. Cebolla ◽  
Pilar Irún ◽  
Ralf Köhler ◽  
Pilar Giraldo
Keyword(s):  
Genetic Variants ◽  
Lysosomal Storage ◽  
Cholesterol Trafficking ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Deleterious Gene ◽  
The One ◽  
Matthew’S Correlation Coefficient ◽  
Sensitivity Specificity ◽  
The Impact

Introduction The growing number of genetic variants of unknown significance (VUS) and availability of several in silico prediction tools make the evaluation of potentially deleterious gene variants challenging. Materials and Methods We evaluated several programs and software to determine the one that can predict the impact of genetic variants found in lysosomal storage disorders (LSDs) caused by defects in cholesterol trafficking best. We evaluated the sensitivity, specificity, accuracy, precision, and Matthew's correlation coefficient of the most common software. Results Our findings showed that for exonic variants, only MutPred1 reached 100% accuracy and generated the best predictions (sensitivity and accuracy = 1.00), whereas intronic variants, SROOGLE or Human Splicing Finder (HSF) generated the best predictions (sensitivity = 1.00, and accuracy = 1.00). Discussion Next-generation sequencing substantially increased the number of detected genetic variants, most of which were considered to be VUS, creating a need for accurate pathogenicity prediction. The focus of the present study is the importance of accurately predicting LSDs, with majority of previously unreported specific mutations. Conclusion We found that the best prediction tool for the NPC1, NPC2, and LIPA variants was MutPred1 for exonic regions and HSF and SROOGLE for intronic regions and splice sites.

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